Induction of Persistent Colitis by a Human Commensal, Enterotoxigenic Bacteroides fragilis, in Wild-Type C57BL/6 Mice

被引：226

作者：

Rhee, Ki-Jong ^{[1
]}

Wu, Shaoguang ^{[1
]}

Wu, XinQun ^{[1
]}

Huso, David L. ^{[2
,6
]}

Karim, Baktiar ^{[2
]}

Franco, Augusto A. ^{[1
]}

Rabizadeh, Shervin ^{[4
]}

Golub, Jonathan E. ^{[1
]}

Mathews, Lauren E. ^{[1
]}

Shin, Jai ^{[1
]}

Sartor, R. Balfour ^{[7
,8
]}

Golenbock, Douglas ^{[9
]}

Hamad, Abdel R. ^{[3
]}

Gan, Christine M. ^{[5
]}

Housseau, Franck ^{[5
,6
]}

Sears, Cynthia L. ^{[1
,5
,6
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21231 USA

[2] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD 21231 USA

[3] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21231 USA

[4] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21231 USA

[5] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21231 USA

[6] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA

[7] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA

[8] Univ N Carolina, Sch Med, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA

[9] Univ Massachusetts, Dept Med, Dept Med, Worcester, MA USA

来源：

INFECTION AND IMMUNITY | 2009年 / 77卷 / 04期

关键词：

INTESTINAL EPITHELIAL-CELLS; INFLAMMATORY-BOWEL-DISEASE; ULCERATIVE-COLITIS; DIARRHEAL DISEASE; FLUID SECRETION; CROHNS-DISEASE; TOXIN GENE; E-CADHERIN; C-MYC; EXPRESSION;

D O I：

10.1128/IAI.00814-08

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Enterotoxigenic Bacteroides fragilis (ETBF) causes diarrhea and is implicated in inflammatory bowel diseases and colorectal cancer. The only known ETBF virulence factor is the Bacteroides fragilis toxin (BFT), which induces E-cadherin cleavage, interleukin-8 secretion, and epithelial cell proliferation. A murine model for ETBF has not been characterized. Specific pathogen-free (SPF) C57BL/6J or germfree 129S6/SvEv mice were orally inoculated with wild-type ETBF (WT-ETBF) strains, a nontoxigenic WT strain of B. fragilis (WT-NTBF), WT-NTBF overexpressing bft (rETBF), or WT-NTBF overexpressing a biologically inactive mutated bft (rNTBF). In SPF and germfree mice, ETBF caused colitis but was lethal only in germfree mice. Colonic histopathology demonstrated mucosal thickening with inflammatory cell infiltration, crypt abscesses, and epithelial cell exfoliation, erosion, and ulceration. SPF mice colonized with rETBF mimicked WT-ETBF, whereas rNTBF caused no histopathology. Intestinal epithelial E-cadherin was rapidly cleaved in vivo in WT-ETBF-colonized mice and in vitro in intestinal tissues cultured with purified BFT. ETBF mice colonized for 16 months exhibited persistent colitis. BFT did not directly induce lymphocyte proliferation, dendritic cell stimulation, or Toll-like receptor activation. In conclusion, WT-ETBF induced acute then persistent colitis in SPF mice and rapidly lethal colitis in WT germfree mice. Our data support the hypothesis that chronic colonization with the human commensal ETBF can induce persistent, subclinical colitis in humans.

引用

页码：1708 / 1718

页数：11

共 61 条

[51] PURIFICATION AND CHARACTERIZATION OF AN ENTEROTOXIN FROM BACTEROIDES-FRAGILIS [J].

VANTASSELL, RL ;

LYERLY, DM ;

WILKINS, TD .

INFECTION AND IMMUNITY, 1992, 60 (04) :1343-1350

[52] Fragilysin, the enterotoxin from Bacteroides fragilis, enhances the serum antibody response to antigen co-administered by the intranasal route [J].

Vines, RR ;

Perdue, SS ;

Moncrief, JS ;

Sentz, DR ;

Barroso, LA ;

Wright, RL ;

Wilkins, TD .

VACCINE, 2000, 19 (06) :655-660

[53] HUMAN COLONIC EPITHELIAL-CELLS, HT29/C1, TREATED WITH CRUDE BACTEROIDES-FRAGILIS ENTEROTOXIN DRAMATICALLY ALTER THEIR MORPHOLOGY [J].

WEIKEL, CS ;

GRIECO, FD ;

REUBEN, J ;

MYERS, LL ;

SACK, RB .

INFECTION AND IMMUNITY, 1992, 60 (02) :321-327

[54] MEDIUM FOR USE IN ANTIBIOTIC SUSCEPTIBILITY TESTING OF ANAEROBIC BACTERIA [J].

WILKINS, TD ;

CHALGREN, S .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1976, 10 (06) :926-928

[55] Bacteroides fragilis enterotoxin induces intestinal epithelial cell secretion of interleukin-8 through mitogen-activated protein kinases and a tyrosine kinase-regulated nuclear factor-κB pathway [J].

Wu, SG ;

Powell, J ;

Mathioudakis, N ;

Kane, S ;

Fernandez, E ;

Sears, CL .

INFECTION AND IMMUNITY, 2004, 72 (10) :5832-5839

[56] Bacteroides fragilis enterotoxin cleaves the zonula adherens protein, E-cadherin [J].

Wu, SG ;

Lim, KC ;

Huang, J ;

Saidi, RF ;

Sears, CL .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (25) :14979-14984

[57] Bacteroides fragilis enterotoxin induces c-myc expression and cellular proliferation [J].

Wu, SG ;

Morin, PJ ;

Maouyo, D ;

Sears, CL .

GASTROENTEROLOGY, 2003, 124 (02) :392-400

[58] Diversity of the metalloprotease toxin produced by enterotoxigenic Bacteroides fragilis [J].

Wu, SG ;

Dreyfus, LA ;

Tzianabos, AO ;

Hayashi, C ;

Sears, CL .

INFECTION AND IMMUNITY, 2002, 70 (05) :2463-2471

[59] Bacteroides fragilis toxin stimulates intestinal epithelial cell shedding and γ-secretase-dependent E-cadherin cleavage [J].

Wu, Shaoguang ;

Rhee, Ki-Jong ;

Zhang, Ming ;

Franco, Augusto ;

Sears, Cynthia L. .

JOURNAL OF CELL SCIENCE, 2007, 120 (11) :1944-1952

[60] The Bacteroides fragilis toxin binds to a specific intestinal epithelial cell receptor [J].

Wu, Shaoguang ;

Shin, Jai ;

Zhang, Guangming ;

Cohen, Mitchell ;

Franco, Augusto ;

Sears, Cynthia L. .

INFECTION AND IMMUNITY, 2006, 74 (09) :5382-5390

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